FI96606B - Process for the preparation of therapeutically useful 2'- ethynyl cytidine, uridine and guanosine derivatives - Google Patents

Description

96606 *

The present invention relates to the preparation of novel 2'-ethynylcytidine, uridine and guanosine derivatives useful as antiviral agents. as anti-inflammatory agents.

This invention relates to the preparation of novel 2'-ethynyl derivatives of formula (Ib)

H0CH2 ^ v \ B

Wherein A is hydrogen, methylene or thio; A 2 is hydrogen and A 2 is a -CsCR group, or A 2 is hydrogen and A 1 is a -CsCR group; wherein R is hydrogen or C 1-4 alkyl; B is a radical of formula "06. ΊΥ Λ"

I I I

wherein Y1 is nitrogen, a CH group, a CC1 group, a CBr group or a CNH2 group; Y 2 and Y 3 are each independently nitrogen or CH; Γ4 is hydrogen, C1-4alkyl, C1-4alkoxy or halogen; 96606 2 Y5 is amino or C1-4 alkoxy; and Z is hydrogen, halogen or NH 2; or a pharmaceutically acceptable salt thereof.

As used herein, the term "halogen" or "halo" means a fluorine, chlorine, bromine or iodine atom and the term "nitrogen" means a trivalent nitrogen atom attached to two radicals. The term "C 1-4 alkyl" means a saturated straight or side chain hydrocarbon radical having from one to four carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl and the like. .

The 2'-ethynyl derivatives of formula (Ib) may be prepared using methods and techniques well known and appreciated by those skilled in the art.

A general synthetic method for the preparation of compounds of formula (Ib) is shown in Scheme D. Scheme D

20

\ H '' j '··· "\\ M' Ύ '\ H] 1 C (OH) -C = CR

O O 0 —0 0 ~~ S i - Si -) - phase a> - 25 W (8) • «30 _- phase b H0 (11)

In step a, a ketone derivative (2), for example 4-35 ethoxy-1 - [(3,5-O-tetraisopropyldisiloxane-1,3-diyl) -yl] When appended to the 3β-D-erythropentofuranosyl] -2 (1H) -pyrimidone, it can be reacted with an acetylene-Grignard reagent such as the general formula RCsCMgBr to give the corresponding 2-ethynyl alcohol (8). Alternatively, 5 alcohols (8) can be prepared from other organometallic compounds prepared from reactive metals, such as the compound represented by the general formula RC = CLi.

A suitable Grignard reagent, or other metallo-10 organic reagent, can be prepared according to methods and procedures well known and appreciated in the art of chemistry, such as those described by J. March in "Advanced Organic Chemistry: Reactions, Mechanisms and Structure". , McGraw-Hill 15 Book Company, 684-98 (1968). For example, a Grignard reagent for acetylene or alkyl-substituted acetylene can be prepared by treating acetylene or alkyl-substituted acetylene with methylmagnesium bromide under anhydrous conditions.

In step b, the 2-ethynyl alcohol (8) is reduced and the tetraisopropyldisiloxane protecting group is removed to give the 2-ethynyl derivative (11). This reduction can be accomplished by methods and procedures well known and appreciated in the chemical art by treating 2-ethynyl alcohol (8) with a reducing agent such as triethylsilane in the presence of an acid such as trifluoroacetic acid.

When a 4-alkoxy-substituted pyrimidone such as 4-ethoxy-substituted pyrimidone is used as a starting material in step a, the 4-alkoxy group of the pyrimidone base can be converted to a 4-keto group to give the corresponding uridine * or thymidine derivative (11) or it can be converted to a 4-amino group. the corresponding cytidine derivative (11) is obtained. These reactions can be performed according to methods well known and appreciated in the chemical art as shown in Scheme A.

96606 4

It will be apparent to one skilled in the art that the 2'-ethynyl derivative (11) may exist as one of the two stereomeric isomers, i. one in which the ethynyl group is on the same side of the furanosyl ring as the 3-hydroxy group 5 and the other in which the ethynyl group is on the same side of the furanosyl ring as the purine or pyrimidine group. For example, when a cytidine derivative is desired, these geometric isomers may be referred to as 2'-deoxy-2 '(R) -ethynylcytidine (or 4-keto-1- [BD-erythropentofuran-2 (R) - (ethynyl) osyl] -2 (1H) -pyrimidone) and 2'-deoxy-2 '(S) -ethynylcytidine (or 4-keto-1- [β-D-erythropentofuran-2 (R) - (ethynyl) osyl] -2 (1H), respectively) -pyrimi-codon).

As will be apparent to one skilled in the art, the (11) (R) and (S) diastereomeric isomers of the 2'-15 ethynyl derivatives can be separated using standard separation techniques. For example, diastereomeric isomers can be separated by column chromatography using known methods and procedures.

The following example illustrates a typical synthesis described in Scheme D. This example is provided for illustrative purposes only and is not intended to limit the scope of this invention in any way. Example 10 2'-Deoxy-2 '(R or S) -ethynylcytidine * Step a: 4-Ethoxy-1 - [(3,5-O-tetraisopropyldisiloxane-1,3-diyl) -BD- (ribo- or arabino) pentofuran-2- (ethynyl) osyl] -2 (1H) -pyrimidone Prepare the title compound.

Step b: 2'-Deoxy-2 '(R or S) -ethynylcytidine Dissolve 4-ethoxy-1 - [(3,5-O-tetraisopropyldisiloxane-1,3-diyl) -BD- (ribo- or arabino -) pentofuran-2-35 (ethynyl) osyl) -2 (1H) -pyrimidone (490 mg, 0.94 nunol) in dichloromethane (3 ml) under a nitrogen atmosphere and I (H t III! I M St 96606 5 Cool the solution in an ice bath (0 ° C). Add trifluoroacetic acid (0.54 mL, 7.08 mmol) followed by triethylsilane (0.27 mL, 1.71 mmol) and stir the solution overnight at room temperature. Dilute the reaction mixture with ethyl acetate-5 (10 mL) and wash with ice-cold 1-norm. sodium hydroxide solution (2 times, 5 ml each time). Dry the organic layer over anhydrous magnesium sulfate and evaporate to dryness to give 4-ethoxy-1- [β-D-erythropentofuran-2 (R and S) - (ethynyl) osyl] -2 (1H) -pyrimidino-10.

Heat a solution of 4-ethoxy-1- [BD-erythropentofuran-2 (R and S) - (ethynyl) osyl] -2 (1H) -pyrimidone (885 mg, 3 mmol) in methanolic ammonia (10 mL, saturated at 0 eC) in a sealed tube at 100 eC for 2 to 15 days. Evaporate the solution to dryness and separate the (R) and (S 2) isomers on a Dowex 1-X 2 (OH 'form) chromatography column to give the title compounds.

The following compounds can be prepared by methods similar to those described in Example 10 above: 2'-deoxy-2 '(R or S) -ethyl-5-methylcytidine, 2'-deoxy-2' (R or S) -ethyl-5 -hydroxymethylcytidine, 2'-deoxy-2 '(R or S) -ethyl-4'-thiocytidine, (±) - (IB, 3α, 4B) -1- (4-amino-2-hydroxypyrimidin-6-yl) -2- (a and B) -ethyl-3-hydroxy-4-hydroxymethylcyclopentane.

Example 11 2'-Deoxy-2 '(R or S) -ethyluridine

Step a: 4-Ethoxy-1 - [(3,5-O-tetraisopropyldisiloxane-30,3-diyl) -ND- (ribo- or arabino) pentofuran-2- (ethynyl) osyl] -2 (1H ) -pyrimidone

Prepare the title compound.

Step b: 2'-Deoxy-2 '(R or S) -ethyluridine 35 Prepare 4-ethoxy-1- [BD-erythropentofuran- (2R and S) - (ethynyl) osyl] -2 (1H) -pyrimidone as described below. described: in Example 10, step b.

96606 6

Stir a solution of 4-ethoxy-1- [β-D-erythro-pentofuran-2 (R and S) -ethyl) osyl) -2 (1H) -pyrimidone (590 mg, 2 mmol) in THF (15 ml) and 1-norm. sodium hydroxide (5 ml) at room temperature for 23 hours and then at 60 ° C for 2 hours. Neutralize the reaction solution with Amberlite IRC-50 (H + form) resin and filter off the resin. Evaporate the filtrate to dryness and separate the (R) and (S) isomers on a Dowex 1-X2 (ΟΗ'-form) chromatography column to give the title compounds.

The following compounds can be prepared by methods similar to those described in Example 11 above: 2'-deoxy-2 '(R or S) -ethyl-5-hydroxymethyluridine, 2'-deoxy-2' (R or S) -ethynylthymidine, 2 '-deoxy-2' (R or S) -ethyl-4'-thiouridine.

Example 12 2'-Deoxy-2 '(R or S) -ethynylguanosine Step a: 9 - [(3,5-O-tetraisopropyldisiloxane-1,3-diyl) -BD- (ribo- or arabino-) pentofuran- 2- (ethynyl) -20-osyl) -guanine

Prepare the title compound from 9 - [(3,5-O-tetraisopropyldisiloxane-1,3-diyl) -2-keto-β-D-erythropentofuranosyl) guanine (2.58 g, 5 mmol).

Step b: 2'-Deoxy-2 '(R or S) -ethynylguanosine “Prepare the title compounds 9 - [(3,5-O-tetraisopropyldisiloxane-1,3-diyl) -BD- (ribo- or arabino -) pentofuran-2- (ethynyl) osyl) guanine as described in Example 10, step b.

The following compounds can be prepared by methods known to those skilled in the art: 2'-deoxy-2 '(R or S) -ethyl-4'-thioguanosine, 2'-deoxy-2' (R or S) -azaguanosine, 2'-deoxy -2 '(R or S) -methylguanosine, 35'-deoxy-2' (R or S) -8-chloroguanosine.

«Il. IHk'i MM l i ^ a ·:; 1 96606 7

In many of the above examples, a 4-ethoxypyrimidone derivative is used as the starting material (2). It will be apparent to those skilled in the art that the 4-ethoxy group may be converted, if desired, to either a keto group (to form a uridine / -5 thymidine derivative) or an amino group (to form a cytidine derivative). Alternatively, if a uridine, thymidine or cytidine derivative is desired, a 2-keto starting material (2) in which the base group is cytosine, uracil or thyrine can be used.

10 The starting materials used in the general synthetic method outlined in Scheme D are readily obtained using synthetic methods and procedures well known and appreciated by those skilled in the art. For example, 4-ethoxy-1 - [(3,5-O-tetraisopropyldisiloxane-1,3-diyl) -2-keto-8-D-erythropentofuranosyl) -2 (1H) -pyrimidone can be used as a starting material for many formulas ( Ib) and can be prepared from uridine according to the method described by Matsuda et al. (Chem. Pharm. Bull. 1988, 36, 20945). 9 - [(3,5-O-tetraisopropyldisiloxane-1,3-diyl) -2-keto-β-D-erythropentofuranosyl) guanine can be prepared from guanosine by methods similar to those described by Hansske et al. (Tetrahedron 1984, 40, 125). Other 2-keto starting materials can be prepared using similar methods described above as well as “conventional methods well known and appreciated in the art, such as the method described by Hansske and Robins (Tetrahedron Lett. 1983, 24, 1589).

Tumor conditions for which treatment with a compound of formula (Ib) is particularly useful include: leukemias, such as (but not limited to) acute early lymphocytic, chronic lymphocytic, acute myoblastic, and chronic myocytic tumors; cancers, including (but not limited to) the neck, esophagus, stomach, small intestine 35, lynkkysuolen and lung cancers; sarcomas, 96606 8 such as (but not limited to) oesteroma, bone sarcoma, resting, adipocyte sarcoma, vascular tumor, and vascular sarcoma; dark cell tumors, including amelanotic and melanotic; and mixed-type neoplasms such as (but not limited to) mixed cancer, lymphoid tissue, follicullar reticulum, cellular sarcoma, and Hodgkins tumor disease. For the treatment of tumor conditions with a compound of formula (Ib), particularly preferred are: 2'-deoxy-2 '(R or S) -ethynylcytidine, 2'-deoxy-2' (R or S) -ethyluridine, 2'-deoxy -2 '(R or S) -ethynylguanosine.

As used herein, the term "patient" means a warm-blooded animal, such as a human, afflicted with a particular tumor or viral disease state.

In addition, the compounds of this invention may be used to treat viral infections. The term "viral infection" as used herein means an abnormal condition or general condition characterized by viral cell transformation, viral replication, and additional growth. Viral infections for which the compound of formula (Ib) is particularly useful include: retroviruses such as, but not limited to, HTLV-I, HTLV-II, human immunodeficiency viruses, HTLV-III (AIDS virus), and the like. viruses; RNA viruses such as, but not limited to, influenza type A, B, and C viruses, mumps, measles viruses; rhinitis virus, dengue fever virus, rubella virus, rabies virus, hepatitis A virus, encephalitis virus and the like; DNA viruses such as, but not limited to, poxvirus, vaccine-rash virus, wart virus, hepatitis B virus, and the like.

A therapeutically effective amount of a compound of formula (Ib) is expected to range from about 0.1 milligrams per kilogram of body weight per day (mg / kg / day) to about 35 mg / kg / day. Preferred amounts are expected to range from about 0.5 to about 10 mg / kg / day.

il IK I joined joins 96606 9

The following list identifies compounds of formula (Ib) which are particularly preferred objects of this invention: 2'-deoxy-2 '(R or S) -ethynylcytidine, 2'-deoxy-2' (R or S) -ethyluridine, 2 '-deoxy-2' (R or S) -ethynylguanosine.

The above list is intended only to illustrate particularly preferred objects of the present invention and it is quite clear that the list does not limit the scope of the invention in any way.

Claims (6)

96606 Claim A process for the preparation of therapeutically useful 2'-ethynylcytidine, uridine and guanosine derivatives of the formula H0CH 2 ^ / v \ HA (Ib) 10 «Xl - [/ H OH where V is oxy, methylene or thio ; A 1 is hydrogen and A 2 is a -C 1 CR group, or A 2 is hydrogen and A 1 is a -C = CR group; wherein R is hydrogen or C 1-4 alkyl; B is a radical of formula 20. Y 06, aV JjT 'i i i 25 • · I · wherein Yx is nitrogen, a CH group, a CC1 group, a CBr group or a CNH2 group; Y 2 and Y 3 are each independently a nitrogen or CH group; Y 4 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy or halogen; Y 5 is amino or C 1-4 alkoxy; and Z is hydrogen, halogen or NH 2; or a pharmaceutically acceptable salt thereof, characterized in that it comprises the steps of: a) 3,5-O-tetraisopropyldisiloxane-1,3-diyl-11β; 4 St; ; 5,960,611 The 2-ketonucleoside derivative is reacted with an acetylene-Grignard reagent to give 3,5-O-tetraisopropyldisiloxane-1,3-diyl-2-ethynyl ± -2-hydroxynucleoside derivative; 5 b) The 3,5-O-tetraisopropyldisiloxane-1,3-diyl-2-ethynyl-2-hydroxynucleoside derivative is reacted with a reducing agent such as triethylsilane to give the corresponding 3,5-O-tetraisopropyldisiloxane-1,3-diyl A 2-ethynyl nucleoside derivative; C) optionally reacting the 3,5-O-tetraisopropyldisiloxane-1,3-diyl-2-ethynyl nucleoside derivative with a base; and d) reacting the 3,5-O-tetraisopropyldisiloxane-1,3-diyl-2-ethynyl nucleoside derivative with a fluoro-15 dianion or acid. • «96606 12 For the preparation of a therapeutically active compound 2'-ethynylcytidine, uridine and guanosine 5 with the formula V B Al A (Ib) 10 h \ | _Y H OH a2 color V är oxi, methyl eller thio; Ax is a member of A2 or a -CsCR group, or a member of A2 is a member of the Axis -C = CR group; color R is a residue or C 1-4 alkyl; It is radical with formula 20. Y5 c6. Xr 25 color Y3 is a group, not a CH group, not a CC1 group, not a CBr group or a CNH2 group; Y2 and Y3 are selected from the group consisting of CH and 30 groups; Y4 is a C 1-4 alkyl, C 1-4 alkoxy or halogen; Y5 is amino or C1-4 alkoxy; and a halogen or NH2; or, in the case of a farmer, a farmer, not less than 35 years old, of which the farmer is a farmer; 9 * il! Ill H HI HI I: - i 13 96606 a) that 3,5-O-tetraisopropyldisiloxane-1,3-diyl-2-ketonucleoside derivatives are reacted with acetylene Grignard reagent to give 3,5-O- tetraisopropyldisiloxane-1,3-diyl-2-ethynyl-2-hydroxynucleoside derivatives; b) that the 3,5-O-tetraisopropyldisiloxane-1,3-diyl-2-ethynyl-2-hydroxynucleoside derivative is reacted with a reagent which reduces the color of the triethylsilane to give 3,5-O-tetraisopropyldisiloxane-1,3 diyl-2-etinylnukleosidderivat; c) optionally cycling the 3,5-O-tetraisopropyldisiloxane-1,3-diyl-2-ethynyl nucleoside derivatives to a reagent; and d) that the 3,5-O-tetraisopropyldisiloxane-1,3-diyl-2-15 ethynyl nucleoside derivative is reacted with fluoride anion or lye. * «»